Targeting the soluble epoxide hydrolase (sEH) enzyme to relieve painful docetaxel-induced peripheral neuropathy.

Abstract

126 Background: Docetaxel is an important chemotherapeutic agent used for the treatment of several cancers, including metastatic prostate cancer. Unfortunately, it shares the side effect profile of other taxanes, including causing painful chemotherapy-induced peripheral neuropathy (CIPN). The pain of CIPN is notoriously difficult to treat, can lead to discontinuation of life-prolonging cancer treatments and can become a debilitating, chronic condition. Notably, African American (AA) cancer patients have increased (2-3-fold) risk and increased severity of CIPN. The enzyme soluble epoxide hydrolase (sEH) functions as a master regulator of inflammation, by converting epoxy fatty acids (EpFAs), which are polyunsaturated fatty acid (PUFA) derivatives with inflammation-resolving, analgesic and anti-cancer properties, into corresponding inactive or pro-inflammatory diols. As sEH inhibition has demonstrated efficacy in several models of neuropathy, here we assessed its potential to relieve and/or prevent docetaxel-induced CIPN specifically. Methods: We established a model of docetaxel-induced painful neuropathy in male Sprague Dawley rats, by administering 3 doses of docetaxel (10 mg/kg intraperitoneally, once weekly, for 3 doses). We tested the efficacy of the small molecule sEH inhibitor EC5026 (EicOsis, Inc, Davis, CA) both (1) as a single dose administered via oral gavage and (2) via chronic administration (1 mg/kg/day) in the drinking water started 1 week prior to and continuing during the period of docetaxel treatments. To examine the analgesic efficacy of EC5026, the rats were assessed for responses in nociceptive (von Frey assay and cold plate assay) and functional (open field test) behavior assays. Tail vein blood was sampled, and the blood concentration of docetaxel (measured by mass spectrometry) was compared between vehicle-treated and EC5026-treated cohorts. Results: Oral dosing of the sEH inhibitor EC5026 dose-dependently relieved docetaxel-induced painful neuropathy. Additionally, chronic treatment with EC5026 via the drinking water blocked both tactile allodynia and cold sensitivity compared to vehicle-treated rats. The open field assay revealed that EC5026 has no negative effect on motor skills. Moreover, EC5026 did not affect the blood levels of docetaxel in rats. Conclusions: sEH is a novel target for achieving pain relief in our CIPN model. Our results indicate robust response to therapeutic treatment of the CIPN model and additionally improved outcomes with prophylactic administration of the sEH inhibitor EC5026 in docetaxel-induced painful CIPN, without effect of EC5026 on animal motor skills or docetaxel pharmacokinetics.